Despite notable achievements over the past two decades, cancer remains a challenging 21st century epidemic demanding new, more effective drugs. Nitric oxide (NO) is well known to kill cancer cells without harming normal bone marrow cells, but until now has not been used directly to treat cancer because of its effect to lower blood pressure. JSK Therapeutics (JSKT) has designed a class of diazeniumdiolate prodrugs that release NO upon interaction with glutathione in a reaction catalyzed by glutathione-S-transferase, which is expressed at significantly higher concentrations in cancer compared to normal cells. JSKT has screened a library of these compounds and has identified one, JS-K, as the most active compound of this family. In the Rapid Access to Intervention Development (RAID) program at the NCI, JS-K is active against the entire "NCI 60-cell" screen. JS-K has potent and broad anticancer activity against solid tumors and hematologic malignancies in multiple laboratories but shows no toxicity against normal bone marrow, making it critically important to the future of cancer therapy. In mouse xenograft models of human tumors, JS-K is highly effective against acute myeloid leukemia, prostate cancer, hepatocellular carcinoma, multiple myeloma and non-small cell lung cancer. Significant work has begun on this promising therapy and has shown that JS-K is difficult to solubilize and has a short half-life in vivo. Previous NIH funding has allowed a solution for these challenges: a stable nanoscale P123 Pluronic(R) micelle intravenous (IV) formulation for JS-K has been developed, and scale- up production and formulation of 1 kg of JS-K in P123 Pluronic(R) micelles is currently under production in compliance with Good Manufacturing Practices. JSKT submits this Fast Track Phase I/II SBIR application to perform the standard acute and subchronic pre-clinical animal toxicology studies needed using Good Laboratory Practices (GLP) to support a successful Investigational New Drug (IND) application to the FDA. JSKT hypothesizes that P123 Pluronic(R) micelle JS-K will prove non-toxic in therapeutic doses needed to treat cancer in humans. In Phase I, JSKT will accomplish 3 deliverables: 1) perform acute IV toxicology of JS-K in rats;2) perform bacterial mutagenicity (Ames) testing;and 3) draft the chemistry and manufacturing section for a JS-K IND application. In Phase II, JSKT will accomplish 2 additional deliverables: 1) develop and validate using GLP procedures a sensitive LS/MS/MS assay for measuring JS-K in biologic fluids;and 2) complete acute IV toxicology studies of JS-K in dogs and 28-day subchronic IV toxicology studies of JS-K in rats and dogs. Upon completion of this project, JSKT will have all the essential pharmacology, toxicology and manufacturing information to submit a successful IND to begin Phase I safety trials of micelle JS-K in humans at the Huntsman Cancer Institute in Salt Lake City, UT. Commercialization of this novel cancer fighting drug, JS-K, will establish a new paradigm in cancer therapy, improve the quality of life for cancer patients and their families with less painful, more effective treatments, and provide a sustainable benefit worldwide. PUBLIC HEALTH RELEVANCE: This project will continue the development of a highly effective new drug called JS-K, which will treat and kill multiple cancers. JS-K will kill these cancers by a new, more selective and measurably less toxic mechanism, making it entirely relevant to today's world. This new drug then goes one step further: it will improve the quality of life for cancer patients, their caregivers and families by providing a significantly more effective and less painful therapy than is currently available.